Innate immune sensing of dietary alcohol ignites inflammation to drive alcohol-related disease 2309590

Abstract Introduction Alcohol is a leading cause of global morbidity and mortality, yet the innate immune sensors that detect alcohol-induced danger signals remain poorly defined. We identify ZBP1 as an innate immune sensor that integrates alcohol exposure with sterile- or infection-induced interferon signaling to trigger inflammatory cell death and promote the development of alcoholic liver disease. Methods Primary murine bone marrow—derived macrophages, human monocytic and liver cell lines, and genetically modified mice were treated with ethanol in combination with interferons. Cell death pathways were assessed using biochemical, molecular, and imaging-based assays. Z-RNA accumulation was quantified by immunofluorescence, dot blotting, and Z-RNA—specific RNA immunoprecipitation. Alcoholic liver disease was examined using murine ethanol-feeding models and human transcriptomic datasets. Results Alcohol synergized with sterile- or infection-induced interferon signaling to induce rapid inflammatory cell death, cytokine release, and liver injury. Combined ethanol and interferon stimulation triggered multiple regulated cell death pathways, including pyroptosis, apoptosis, and necroptosis. The innate immune sensor ZBP1 was essential for this response, as genetic ablation of the innate immune sensor ZBP1 protected cells and mice from cell death and alcoholic liver pathology. Mechanistically, interferon induced ZBP1 expression, whereas ethanol suppressed the RNA-editing protein ADAR1, promoting cytosolic Z-RNA accumulation. Alcohol and interferon converged on JNK signaling to induce endogenous Z-RNA, which activated ZBP1 via its Zα2 domain to drive inflammatory cell death. Conclusion These findings identify ZBP1 as a central innate immune sensor that integrates alcohol-induced stress and interferon signaling to drive Z-RNA—dependent inflammatory cell death and alcoholic liver disease, providing mechanistic insight and highlighting potential therapeutic targets for alcohol-related disease. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)